1-(Methoxymethyl)benzoimidazole → {3-[5-Fluoro-3-(tetrahydro-pyran-4-YL)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-YL)-methanone

HRID 1846790Notes

Reaction equation

HRID 1846790 reaction equation
[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:26][CH:25]([O:27][C:28]2[C:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][C:31]([F:40])=[CH:30][N:29]=2)[CH2:24]1)=[O:22]>C1COCC1>[F:40][C:31]1[CH:32]=[C:33]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:28]([O:27][CH:25]2[CH2:26][CH:23]([C:21]([C:5]3[N:4]([CH2:3][O:2][CH3:1])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:6]=3)=[O:22])[CH2:24]2)=[N:29][CH:30]=1

Participants

5

Reactant 3

HCID 15402701-(Methoxymethyl)benzoimidazoleHCID 585485673-[5-Fluoro-3-(tetrahydro-pyran-4-YL)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methoxy-methyl-amideHCID 178418339Butyllithium

Product 1

HCID 67481419{3-[5-Fluoro-3-(tetrahydro-pyran-4-YL)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-YL)-methanoneYield 39.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5 g, 9.04 mmol) in THF (20 mL) at −78° C. was added butyllithium (2.5 M in hexane) (3.7 mL, 9.16 mmol). The solution was stirred at −78° C. for 30 min and a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methoxy-methyl-amide (2.2 g, 6.87 mmol) in THF (20 mL) was added dropwise via cannula. The reaction mixture was stirred at −78° C. for 30 min and then warmed to RT and quenched with water. The reaction mixture was extracted with EtOAc (3×25 mL) and the organic phases were combined and washed with water (1×10 mL), brine (1×10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes) to give the product (1.2 g) as yellow oil.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 30 min
  2. temperaturewarmed to RT
  3. customquenched with water
  4. extractionThe reaction mixture was extracted with EtOAc (3×25 mL)
  5. washwashed with water (1×10 mL), brine (1×10 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto get a residue, which
  10. customwas purified by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-8d9325ab4a1049fbb70d5cba1e57b9eb
Source dataset
uspto-grants-2015_02
Patent number
US08952037B2

Reaction notes

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